Intrauterine growth restriction (IUGR) complicates 4 to 7% of all pregnancies in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is fundamental to the majority of cases of IUGR in humans. Both faulty trophoblastic invasion of the maternal spiral arteries as well as vasoconstriction of the maternal vasculature may contribute to suboptimal uteroplacental perfusion. Faulty trophoblastic invasion, however, does not fully account for decreased uteroplacental perfusion and consequent IUGR because placental perfusion and fetal growth may be normal where faulty trophoblastic invasion is observed. Further, not all cases of IUGR associated with decreased uteroplacental perfusion have histologic evidence of faulty trophoblastic invasion. Vasoconstriction of the maternal vasculature contributes to the decreased uteroplacental perfusion commonly observed in cases of IUGR. Suboptimal placental perfusion (i.e. ischemia) results in the release of vascular mediators that may further compromise placental perfusion. The contribution of vasoactive mediators to the decreased uteroplacental perfusion commonly observed in human IUGR is not known. The recently developed uterine ischemia/reperfusion (I/R) model of IUGR in the rat is uniquely suited to study the contribution of vascular mediators to decreased uteroplacental perfusion. Temporary uterine ischemia in one of the two horns of the gravid rat uterus results in IUGR not just in one but in both horns, presumably as a result &circulating mediators. Endothelin-I (ET-1), a locally active vasoconstrictor, contributes to the regulation of uterine and placental vascular tone. We hypothesize that ET-1 plays a primary role in the pathophysiology of fetal growth restriction. Ischemia is a potent stimulus to ET-1 production, and ET-1 is up-regulated in IUGR both in humans and in animals. Beyond its direct vasoconstrictive effects, ET-1 also upregulates the production of platelet activating factor (PAF), a potent vasoactive and inflammatory mediator. ET-1 and PAF may act synergistically to decrease local perfusion. Therefore, we will evaluate the contribution of these two key mediators to the pathophysiology of I/R-induced IUGR. We have previously demonstrated that ET-I plays a primary role in two other models of IUGR. We now propose to evaluate the synergistic role of endogenous ET-1 and PAF in ischemia-induced IUGR, and to investigate the molecular mechanisms regulating their activities. Our goal is to assess the specific role of ET-1, as well as its interaction with PAF, in the pathophysiology of I/R-induced IUGR.